Patients with thyroid crisis almost universally need fluid resuscitation. Mindfully replace fluid with careful attention to the patient during the resuscitation.
Myxedema coma is a critical physiologic state. Mortality is high, even with early recognition and aggressive treatment. In multiple case series, patients older than 60 years and patients with cardiovascular decompensation had higher mortality rates.8,64-66
The treatment of myxedema coma is intravenous replacement of thyroxine.66 Intravenous preparations of T4 and T3 are available. T4 has been considered the safer preparation, as intravenous T3 classically has been related to cardiac ischemia and arrhythmias. However, there is little published research in the past 30 years to support this concern. One recent case series of 8 patients treated with high-dosage intravenous T3 (75-175 μg initially, followed by 150 μg) showed a high mortality, with 7 of 8 patients dying.65 These researchers also performed a case review in which they determined that high-dosage intravenous T3 and T4 are related to increased mortality. Recent research on cardiac patients treated with intravenous T3 raises questions about the concerns regarding giving intravenous T3. Studies of patients with cardiac disease have not supported the concern for adverse cardiac effects of intravenous T3. One study in which intravenous T3 was administered to 23 patients with congestive heart failure showed no cardiac ischemia or arrhythmias.67 In another study, 30 patients undergoing coronary artery bypass grafting were administered T3 intravenously (IV) without evidence of ischemia or arrhythmia.68 Importantly, these patients were not in decompensated hypothyroid states, so the data cannot be directly extrapolated.
T4 is administered in a dosage of 200 to 500 μg IV (pediatric dosage 10 mcg/kg/d IV divided q6- 8). It has been well established by multiple classic studies and a recent study that the administration of T4 achieves therapeutic levels of T3 and clinical reversal of myxedema.69,70 A study done in 1976 showed 100% survival of 7 patients with myxedema who were treated with high-dosage intravenous T4 (300-500 μg).71 Yamamoto's case survey suggests that high-dosage intravenous T4 is related to higher mortality.72 A more recent, prospective, randomized study of 11 patients compared an intravenous highdosage (500 μg) load of T4 followed by the standard 100 μg dosage intravenous maintenance with a 100 μg maintenance dosage without a loading dose.8 In this study, 3 of the 4 deaths were patients who did not receive a loading dose. The numbers were not sufficient to reach statistical significance. One case report describes the successful treatment of a patient with myxedema coma with oral doses of T4 given via nasogastric tube.73 Debate continues regarding the optimum intravenous dosage of T4.
Researchers are revisiting the role of combination T4 and T3 therapy in stable patients with hypothyroidism. To date, most studies have not shown a measurable physiologic or emotional improvement with combination therapy.70,74,75 However, 2 prospective studies, conducted by the same group, show improved reversal in symptoms of hypothyroidism with combined T4 and T3 therapy.76,77 It is unclear how these recent studies will affect recommendations for the treatment of the patient with myxedema. One group proposes combination therapy of intravenous T3 and T4 for the patient with myxedema.78
Empiric glucocorticoids are recommended by some groups, as hypopituitarism and hypoadrenalism can mimic myxedema coma. In addition, thyroxine supplementation can leave a patient with relative adrenal insufficiency.79,80 However, there is little research to support this recommendation. A stress dose of hydrocortisone at 100 mg IV (pediatric dosage 0.5-1 mg/kg IV q8) is the recommended dose. Send a random serum cortisol before administration of glucocorticoids to help in the subsequent endocrinologic evaluation of the patient. Hypothermia corrects with the normalization of basal metabolic rate. In the ED, warmed blankets are generally sufficient therapy for a mildly hypothermic patient.
Decreased oral intake due to slowed metabolism and secondary processes such as sepsis cause dehydration in most patients with myxedema coma. However, the associated bradycardia and any underlying cardiac disease make fluid replacement a complex endeavor. The physician should carefully monitor the patient's response to fluid with invasive monitoring, frequent physical examination, bedside ultrasonography, or a combination of the above to prevent hypervolemia and pulmonary edema.
Patients with myxedema coma may require intravenous vasopressors to support their cardiovascular status. When possible, avoid vasopressors with strong alpha-adrenergic effects (phenylephrine and norepinephrine). The chronic state of hypothyroidism is believed to result in reduced beta-adrenergic receptors. The result is a beta- to alpha-adrenergic receptor misbalance. 81 Dopamine, because it has a lower a-effect, is the recommended first-line vasopressor.138 There is no evidence to support this recommendation.
Intervention in thyroid storm requires a three-step treatment approach. First, treat the peripheral effects of the hyperthyroidism. Second, prevent further synthesis of thyroid hormone with antithyroid medications. And third, prevent further release of thyroid hormone. (See Table 7.)
Beta-blocking agents reduce the systemic effects of excess thyroid hormone. If the patient shows cardiovascular stability and has mild symptoms, such as mild tachycardia and tremor, an oral beta-blocking agent can be chosen. If the patient has a more dramatic presentation, such as signs of cardiovascular instability, chest pain, or altered mental status, intravenous beta-blockers are required. Based on case reports, initial stabilization with short-acting beta-blocking agents that are titrated to effect is the preferred method of treatment.82,83 Although the use of propanolol for beta-blockade has been related to bad outcomes, it does have the physiologic advantage of decreasing peripheral conversion of T4 to T3 that other beta-blocking agents have not been demonstrated to possess.52
The fever related to thyroid storm and underlying infection contributes to tachycardia. This can worsen cardiovascular dynamics, and it complicates the physician's assessment of the patient's volume status. Antipyretics are indicated to treat fever. Acetaminophen is the antipyretic of choice. Textbooks recommend avoiding aspirin, as it increases free T3 and T4 concentrations because of protein binding. Although aspirin overdose has been linked to thyroid storm, there is little research on the clinical effect of therapeutic doses of aspirin.84
High output failure poses one of the most difficult treatment scenarios in thyroid storm. The patient has pulmonary edema usually in the setting of volume depletion. For this reason, diuretics should be avoided. The patient needs increased intravascular volume. Diuretics would reduce intravascular volume, possibly precipitating a hypotensive event. The inciting event in high output heart failure is tachycardia. To improve hemodynamics, the heart rate must be slowed to allow increased cardiac filling time. beta-blockade of the heart will slow the heart and allow the appropriate filling time. The decision to use beta-blockers can be difficult in a patient who has pulmonary edema and hypovolemia and may have underlying car iac hypomotility. A continuous infusion of a short-acting beta-blocker is preferred for this reason. The starting dose and decision to use a loading bolus is controversial. Ventilation with noninvasive positive airway pressure can facilitate the redistribution of pulmonary edema without the use of diuretics. It is difficult to balance pulmonary edema and fluid replacement. Judicious replacement of fluid while monitoring the patient's response to fluid with invasive monitoring, frequent physical examination, and bedside ultrasonography is the best approach.
Thioureas, propylthiouracil (PTU), and methimazole block the synthesis of thyroid hormone in the thyroid. PTU is the only thioureas approved for use in pregnancy. PTU is loaded in a dosage of 600 to 1000 mg orally, then 200 to 300 mg orally every 4 to 6 h for a total of 1200 mg per day (pediatric dosage 5-7 mg/kg per day divided q8). The methimazole dosage is 20 mg orally or rectally every 4 h (pediatric dosage 0.4-0.7 mg/kg per day divided q8 to q24). There is no parenteral dose of thioureas. PTU is the less expensive thiourea and has the added therapeutic benefit of inhibiting the conversion of inactive T4 to physiologically active T3 in the serum.
Corticosteroids also block the peripheral conversion of T4 to T3. Dexamethasone is the most effective corticosteroid, administered in a dosage of 2 mg IV every 6 h. An alternative is hydrocortisone 100 mg IV every 8 h.51 Dexamethasone offers the advantage of not affecting subsequent adrenal testing. There is no significant cost differential.
Prevention of further thyroid hormone synthesis is the final step in the intervention in thyroid storm. Inorganic iodine is used to block the synthesis of thyroid hormone. The timing of this therapy is important. This treatment must follow the administration of thiourea by at least 1 h. If iodine is administered earlier than this, it stimulates the release of thyroid hormone from the thyroid, worsening the hyperthyroidism. Iodine is available in many oral forms. Saturated solution of potassium iodide or Lugol solution in doses of 6 to 8 drops every 6 to 8 h are effective. (The dosage of potassium iodide and Lugol solution is the same in the pediatric patient.) The contrast dyes can be administered. Iohexol is an intravenous formulation administered 600 mg IV every 12 h. Oral iodinated contrasts can also be administered; these have a safer renal side effect profile. An example of an oral contrast agent is iopanoic acid; it is administered 500 mg orally twice daily. Consult a pediatric endocrinologist for appropriate dosing of contrast agents in pediatric patients.85-88 In the setting of an iodine allergy, use lithium carbonate 300 mg orally every 6 h (pediatric dosage 15-60 mg/kg divided q8 orally). The optimum agent is the agent that is most readily available and familiar to the pharmacist mixing the drug.